Clinical Research Directory

Development of 4D Flow MRI for Risk Stratification of Variceal Bleeding in Cirrhosis

The goal of this research is to validate novel non-invasive Magnetic resonance imaging (MRI) biomarkers to detect Gastroesophageal varices (GEV) in patients with cirrhosis, including fractional flow change in the portal vein and elevated azygos flow. End-stage liver disease (cirrhosis) is characterized by advanced fibrosis, liver failure, and portal hypertension. There are many causes of cirrhosis, including viral hepatitis, alcohol abuse, and perhaps most importantly, non-alcoholic fatty liver disease (NAFLD) and its aggressive subset, non-alcoholic steatohepatitis (NASH). 3 million new cases of end-stage liver disease (cirrhosis) are expected over the next decade. In cirrhosis, portosystemic collaterals that shunt blood away from the liver develop due to increased portal pressure. Gastroesophageal varices (GEV) are the most clinically relevant because they can cause fatal internal bleeding. GEV bleeding carries \~20% mortality at 6 weeks, and \~34% overall mortality. Identification of at-risk varices, prior to bleeding, is of paramount importance to initiate primary prophylaxis. To identify and treat at-risk patients, current guidelines recommend regular esophagogastroduodenoscopy (EGD) and variceal band ligation. Detection of high-risk GEV is key to initiating primary prophylaxis, which can reduce mortality by 50-70%. However, endoscopy is invasive and often unnecessary when no treatment is required. Therefore, the American Association for the Study of Liver Diseases has identified the development of "non-invasive markers that predict the presence of high-risk varices" as a major unmet need.

Online Prehabilitation for Patients Awaiting Liver Transplantation

Physical frailty is common in patients awaiting liver transplantation and has been associated with poor health outcomes. There is promising data from small studies showing that behavioural, nutrition, exercise therapy (prehabilitation) improves physical function in patients while they are waiting for a liver transplant. The proposed trial will assess if a 12-week online prehabilitation program improves physical function in patients listed for liver transplantation. Over 4 years, 177 patients will be recruited from 6 transplant centres across Canada and will be randomized to receive either the online prehabilitation program or usual care. The primary outcome of physical function will be evaluated using the FTSST at baseline and 12 weeks (or last timepoint before transplant) assessed virtually or in-person. Secondary outcomes include liver specific physical frailty, aerobic fitness, health-related quality of life (QoL), participant experience and acceptability. Exploratory outcomes include other virtual and in-person physical function measures, covert hepatic encephalopathy (CHE), sarcopenia, malnutrition, adherence, behaviour factors, clinical and post-transplant outcomes. Results will be compared between the intervention and usual care groups.

Effect of Fufang Biejiaruangan Combined With Antiviral Therapy on the Incidence of Hepatocellular Carcinoma in Patients With Hepatitis B-related Cirrhosis: A Multicenter, Randomized, Placebo-controlled Study

This study aims to establish a prospective, multicenter, randomized, double-blind, placebo-controlled parallel-group clinical trial cohort. The cohort will include high-risk populations for hepatitis B cirrhosis-related hepatocellular carcinoma (HCC) from multiple centers nationwide, who meet the criteria of traditional Chinese medicine syndrome differentiation as Qi-zhi-xue\_yu syndrome and have an aMAP score \>60 points. The objective is to evaluate whether combining Bie-jia-ruan-gan with standard anti-hepatitis B virus therapy can further reduce the incidence of HCC in this high-risk population.

Initial Resuscitation for Acute Kidney Injury in Cirrhosis

The goal of this interventional study is to evaluate two strategies for how to provide intravenous (IV) fluids for treating patients with acute kidney injury (AKI) in cirrhosis. The main question it aims to answer is: what is the safety, efficacy, and feasibility of providing a recommendation to use a Volume Assessment Guidance Algorithm (VAGA) or give standard of care doses of IV albumin? Patients will be randomly assigned where their treating teams will receive a VAGA-based recommendation or a standard of care IV albumin recommendation.

Transitional Care Program for Fluid Overload in Cirrhosis

The goal of this clinical trial is to learn about an intensive monitoring plan (transitional care program) in patients with cirrhosis and excessive swelling that are going to be discharged from the hospital. The main question\[s\] it aims to answer are: * How much time and what resources are needed to run such a program * How well do patients follow up with the phone calls, bloodwork, and doctor appointments? * Do the patients enrolled in the program have less need for hospitalization later, less kidney injury, better fluid control, and/or better survival compared to patients that are not in the program? Participants will * Be given a digital scale and a binder with educational material and a log to monitor their weights after discharge from the hospital * Receive a phone call from the study team within 72 hours of discharge and weekly * Be given a follow up appointment with hepatology within 4 weeks of discharge Researchers will compare participants in this program to patients that receive normal care to see if there are differences in need for hospitalization later, kidney injury, fluid control, and/or survival.

LiveSMART Trial to Prevent Falls in Patients With Cirrhosis - Supplementary Study

The LIVE-SMART supplementary study will assess social determinants of health (income, education, neighborhood deprivation), financial burden (out-of-pocket costs, productivity loss), financial distress (patient and caregiver-reported outcomes), and financial toxicity (healthcare utilization) among LIVE-SMART participants and their caregivers. Participants for this supplementary study are participants in the primary study (NCT05794555) and their caregivers.

Liver Cancer Prevention Randomized Control Trial

To determine the effectiveness of a behaviorally-based tailored disease management intervention in patients with fibrosis or steatosis and risk factors for cirrhosis.

Changes in Bile Acids and Microbiota in Patients With Hepatitis D Treated With Bulvertide

HDV is an RNA virus that infects only in the presence of HBV, affecting about 13% of HBsAg carriers. In Italy, prevalence ranges from 3.2% to 9.3%. It increases the risk of cirrhosis, fulminant hepatitis, and HCC, particularly in high-risk groups (HIV, HCV, drug users, dialysis patients). Until 2020, pegIFN was the only therapy; since 2022, bulevirtide (BLV) has been available, blocking viral entry into hepatocytes and reducing HDV RNA and liver stiffness, with efficacy in 45-48% of patients, though the optimal treatment duration remains uncertain. The gut microbiota and bile acids also play a role in fibrosis and cirrhosis progression: dysbiosis, typical in cirrhotic patients, alters bile acid metabolism and increases intrahepatic toxicity.

Cirrhotic and Non-cirrhotic Patients With Clinically Significant Portal Hypertension

Alterations in conventional coagulation tests in patients with cirrhosis and/or portal hypertension do not reliably predict bleeding risk, as hemostatic balance is complex and often compensated. Many procedure-related bleeding events are driven by non-coagulatory factors, such as portal hypertension or technical aspects of the procedure. Most commonly performed procedures carry a low risk of bleeding even in the presence of elevated INR or thrombocytopenia, and no validated laboratory thresholds support prophylactic correction. Risk assessment should therefore be based on procedural factors, severity of liver disease, and systemic patient conditions, with correction of modifiable risk factors particularly before high-risk elective procedures.

ALTA TIPS: A 5-year Longitudinal Observational Study of Patients Undergoing TIPS Placement

ALTA is a multicenter consortium focused on the management of portal hypertension. ALTA TIPS is a longitudinal observational study of patients who are undergoing transjugular intrahepatic portosystemic shunt (TIPS) placement. ALTA will create a database that will provide clinical parameters and outcomes of patients undergoing TIPS as part of their standard of care in hopes of answering key clinical questions.

3D-MRE for Assessing Cirrhosis, Advanced Chronic Liver Disease and Portal Hypertension

How to construct a novel, non-invasive, accurate, and convenient method to achieve prediction of hepatic venous pressure gradient (HVPG) is an important general problem in the management of portal hypertension in cirrhosis or advanced chronic liver disease. We plan to investigate the ability of three demensional-magnetic resonance elastography (3D-MRE) to establish a risk stratification system and perform tailored management for portal hypertension in cirrhosis or advanced chronic liver disease.

Prophylactic Antibiotics in Endoscopic Secondary Prevention of Gastroesophageal Variceal Bleeding

Whether prophylactic antibiotics should be administered in the endoscopic secondary prevention of GVB or not is unclear. In this non-inferiority trial, we are aimed to evaluate whether prophylactic antibiotics are essential in the endoscopic secondary prevention of cirrhotic patients with gastroesophageal variceal bleeding.

RTX001 Autologous Engineered Macrophages for Liver Cirrhosis

The purpose of this study is to assess the safety and efficacy of RTX001 in patients with end-stage liver disease. This study is the first time RTX001, a macrophage cell therapy engineered to have an anti-inflammatory and anti-fibrotic effect, will be given to humans.

Diagnosis of Lymphohistiocytic Hemophagocytosis in Intensive Care

Patients with hepatocellular insufficiency and/or cirrhosis are at risk of developing invasive fungal infections, particularly in critical care settings. In international recommendations, voriconazole is positioned as the first-line treatment for invasive aspergillosis. However, this molecule-and the azole class of antifungals-is associated with frequent hepatic toxicity. Available since 2018, isavuconazole appears to be better tolerated in patients without pre-existing liver dysfunction. The aim of this study is to retrospectively evaluate the validity of the hscore in intensive care and resuscitation patients.

Liver Cirrhosis Network Rosuvastatin Efficacy and Safety for Cirrhosis in the United States

This is a double-blind, phase 2 study to evaluate safety and efficacy of rosuvastatin in comparison to placebo after 2 years in patients with compensated cirrhosis.

Liver Cirrhosis Network Cohort Study

Liver Cirrhosis Network (LCN) Cohort Study is an observational study designed to identify risk factors and develop prediction models for risk of decompensation in adults with liver cirrhosis. LCN Cohort Study involves multiple institutions and an anticipated 1200 participants. Enrolled participants will have study visits every 6 months (180 days), with opportunities to complete specific visit components via telehealth or remotely. Visits will include collection of questionnaire data and the in-person visits will include questionnaires, physical exams, imaging, and sample collection.

Study of Tremelimumab and Durvalumab (MEDI4736) (T300+D) in Advanced Hepatocellular Carcinomas With Child-Pugh-B Cirrhosis

This is a single-arm, phase II study of patients with advanced liver cancer or hepatocellular carcinoma (HCC) who are eligible for first-line treatment with T300+D. The invesitgators hypothesize that T300+D will be safe and tolerated in CP-B patients with HCC. HCC mostly affects disadvantaged populations with higher rates among racial/ethnic minorities, who are often not included in clinical trials (i.e., Hispanics, Blacks, underserved, low socioeconomic status) and present with more severe disease. Given there is not much data in the US patient cohort, this study provides a chance to gain that knowledge.

Intraabdominal Hypertension and Occurrence of Microaspiration in Cirrhotics Under Mechanical Ventilation

The study aims to demonstrate the relationship between intra-abdominal hypertension (IAH) and abundant microaspirations in mechanically ventilated cirrhotic.

Echocardiography-guided Cirrhosis and Liver Failure-Intensive Care Protocol Sepsis

* Point-of-care echocardiography is used to guide septic shock resuscitation in patients with severe sepsis in the intensive care unit (ICU), but without systematic evidence for efficacy in critically patients with Cirrhosis and Severe Sepsis. * Due to portal hypertension, these patients have a hyperdynamic circulation, increased capillary permeability, splanchnic arteriolar vasodilation, reduced effective circulating blood volume and may have latent cirrhotic cardiomyopathy (CCM). * Hence assessment of volume status and cardiac reserve using conventional central venous pressure (CVP) or mean arterial pressure (MAP) remains difficult. Novelty: * In two recent trials, the role of 5% albumin vs PlasmalyteTM (FRISC study)(1) and 20% albumin vs. PlasmalyteTM (ALPS study) (2) were reported as the primary resuscitation fluid. Neither trial showed a clear long term survival benefit of albumin over balanced salt solution (BSS). In fact, the ALPS trial reported that there was increased risk of pulmonary edema with use of 20% albumin as fluid resuscitation. * A major limitation of such trial data is that the focus is on choice of fluid rather than looking at hemodynamic goals of resuscitation, resulting in protocolized overzealous fluid administration. * This may result in albumin-related pulmonary edema, and precipitation of overt heart failure in patients with silent CCM. * POC-Echo-based fluid resuscitation can prevent pulmonary edema and consequently respiratory failure, while ensuring renal and tissue perfusion. * It is unclear if choice of fluid or appropriate targets of resuscitation drive the survival benefit in the intensive care management of cirrhosis with severe sepsis. Objectives: * The investigators will conduct an ICU based randomised controlled feasibility trial comparing two measures of resuscitation: Echocardiography (ECHO) Guided septic shock resuscitation vs. a modified Goal-Directed Fluid Therapy (GDT) as recommended by sepsis guidelines which use protocol fluids. * The study will validate the role of POC-Echo parameters as volume assessment tools (cardiac index, systemic vascular resistance index) to determine endpoints of fluid resuscitation and need for vasopressors. * Lastly, the study aims to determine the presence of CCM in this population, and its impact on clinical outcomes. Methods POC-ECHO will be done within 1 hours of admission to the liver ICU and at 24h, 48 h and 72 hours in patients with cirrhosis with systolic blood pressure of \<90 mmHg or a mean arterial pressure \<65 mmHg. Resuscitation target is maintenance of MAP ≥65 mmHg with use of fluids and/or vasopressors. Clinical, cardiac biomarkers, and survival data based on resuscitation fluids will be prospectively collected. CCM will be defined as per CCM Consortium (2020) criteria. Expected outcome. The key questions to be answered in the resuscitation of critically ill patients with cirrhosis and sepsis induced hypotension are: 1. What should be best method of ensuring adequate fluid resuscitation i.e. fluid resuscitation protocol? 2. Which measurable clinical parameter can be used to determine adequacy of fluid resuscitation, and as a predictor of mortality outcomes at 7 and 28 days? 3. Whether early fluid resuscitation translates into better clinical outcome in decreasing duration of hospital and intensive care unit (ICU) stay, prevention of AKI and prevention of secondary sepsis?

Molecular Mechanism of Exercise in Cirrhosis

This study aims to investigate the effects of 12 weeks of resistance or endurance exercise on patients with cirrhosis. Cirrhotic patients are prone to muscle loss (sarcopenia) and ammonia build up due to liver dysfunction. The liver which in healthy patients is able to process ammonia through ureagenesis is unable to do so in cirrhosis and ammonia is taken up either by the brain causing confusion or the skeletal muscle causing muscle loss or sarcopenia. Primary sarcopenia occurs in older individuals and can be mitigated by exercise. Secondary sarcopenia occurs in response to disease such as cancer, chronic kidney disease, multiple sclerosis, and cirrhosis of all etiologies. Resistance exercise is an excellent stimulator for muscle protein synthesis and is widely used to build muscle mass and strength but has little benefit to cardiovascular function. Endurance exercise has shown to be safe in cirrhosis however there is no set prescription for cirrhosis as there is for other disease. Endurance exercise is known to promote improved cardiovascular health, improve fatigue, and generates less ammonia build up than resistance exercise. In patients with low muscle mass it is possible that endurance exercise alone will be enough to improve muscle mass. There have been few studies on exercise and cirrhosis, those that exist have shown benefits with endurance exercise. However there are even more limited studies on resistance exercise and few to no studies on the molecular mechanisms behind exercise in cirrhosis. Study visits are described fully in the protocol and consent form. After passing a screening visit patients will undergo a maximal exercise/fitness test (pre-baseline test) and other body composition measurements. After the screening and pre-baseline visit randomization will occur (2:2:1 endurance, resistance, or SOC) arrangements will be made to have the appropriate exercise equipment given to patients. Once the exercise equipment has arrived a baseline study visit will occur. After the baseline visit the endurance exercise group will cycle 3 days per week for 60 minutes under the supervision of the study team. The resistance exercise group will perform a whole body resistance workout 2 days per week for approximately 60 minutes under the supervision of a study team member. Patients in all groups will have the fitness test repeated at weeks 4, 8 and 12. After the 12 weeks of exercise the baseline visits will be repeated and after 2 weeks patients will complete one final fitness test to examine the effects of de-training.

HMB Enriched Amino Acids to Reverse Muscle Loss in Cirrhosis

Loss of skeletal muscle mass or sarcopenia is the most common and potentially reversible complication in cirrhosis that increases morbidity and mortality before, during and after liver transplantation. No proven treatments exist for the prevention or reversal of sarcopenia in cirrhosis, primarily because the mechanisms responsible for this are unknown. Based on compelling preliminary studies and those of the co investigator, investigators hypothesize that the mechanism of reduced skeletal muscle mass in cirrhosis is due to a myostatin mediated impaired mTOR (mechanistic target of rapamycin) signaling resulting in reduced protein synthesis and increased autophagy. Investigators further postulate that leucine, a direct stimulant of mTOR, will reverse the impaired mTOR phosphorylation in the skeletal muscle of cirrhotics. The consequent increase in protein synthesis reduced autophagy will result in an increase in skeletal muscle mass. Investigators will test these hypotheses by quantifying the response to acute and long term (3 month) administration of hydroxymethyl butyrate (HMB) enriched essential amino acid compared with an isonitrogenous isocaloric non-essential balanced amino acid mixture (does not stimulate protein synthesis) in cirrhotic patients. Fractional protein synthesis rate (FSR) in skeletal muscle, responses of the molecular regulatory pathways of skeletal muscle protein synthesis, and autophagy flux will be quantified in the acute and long term protocols. Tracer studies using L-\[D5\]-phenylalanine (Phe) as a primed constant infusion (prime 2µmol.kg-1.hr-1; constant 0.05 µmol.kg-1.hr-1) with and L \[ring-D2\] tyrosine, forearm plethysmography, and sequential skeletal muscle biopsies (total of 3 per study subject) will be used to quantify these outcomes. Anthropometric, clinical and body composition measures will be additional outcome measures for the long term intervention. Expression of regulatory signaling proteins, myostatin, IGF-1 (insulin like growth factor) , phospho-Akt, phospho-AMPK (activated protein kinase), phospho-mTOR and phospho-p70s6k will be quantified by Western immunoblots. Autophagy flux will be measured by quantifying expression of the autophagosome proteins.

A Study of SIPLIZUMAB in AILD and LT Patients

There is a significant unmet need for safe and effective therapeutic approaches to prevent immune-mediated graft injury and its complications in liver transplant (LT) recipients with autoimmune liver disease (AILD) including autoimmune hepatitis and primary sclerosing cholangitis. Siplizumab is an anti-cluster of differentiation 2 (CD2) monoclonal antibody that has demonstrated a favorable safety profile of siplizumab in over 779 human subjects and has been shown to target memory T cells-a key driver in the immune processes surrounding rejection and autoimmunity post LT in AILD. The purpose of this pilot, open-label phase 1 study is to determine the safety of siplizumab for induction in patients with AILD undergoing LT. Up to eight (8) subjects will receive siplizumab 0.6 mg/kg/dose on the day of transplant (Day 0) and Day 4 post-transplant, for a total of two doses. All subjects will be followed in the study for 12 months post-LT.

Erlotinib for Hepatocellular Carcinoma Chemoprevention

This phase II randomized placebo-controlled trial studies low-dose erlotinib treatment to assess its efficacy and safety to prevent development of hepatocellular carcinoma in patients with advanced liver fibrosis or cirrhosis.

The Microbiota Augmentation to Reestablish Commensal Organisms (MARCO) Trial

The Microbiota Augmentation to Reestablish Commensal Organisms (MARCO) trial is a single center prospective adaptive phase 1b clinical trial in patients who are hospitalized with complications of liver disease and have low fecal metabolite levels (butyrate and deoxycholic acid). The study intervention is 1 of 9 novel live Commensal Consortia each containing eight commensal bacterial strains derived from healthy donors. The primary objective of the study is to determine safety and tolerability of Commensal Consortia administration.